We have been conducting a comprehensive genotype-phenotype correlation study in patients with the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region. We had previously observed that haploinsufficiency for BDNF, the gene which encodes brain-derived neurotrophic factor, is associated with higher prevalence of childhood obesity and higher scores on a hyperphagia questionnaire (N Engl J Med 2008;359(9):918-27). BDNF is widely expressed throughout the nervous system and plays an important role in neuronal development and synaptic plasticity. In animal studies, BDNF appears to function downstream of the leptin signaling pathway to regulate appetite and energy balance. Our findings support the role of BDNF in human energy homeostasis. We have been conducting further studies to characterize the role of BDNF in neurocognitive function because Bdnf+/- mice are not only hyperphagic and obese, but also display learning deficits, behavioral abnormalities, and decreased thermal pain response. We have observed that among subjects with WAGR syndrome, BDNF haploinsufficiency is associated with 14-point lower Vineland Adaptive Behaviour Compose score and 20-point lower intelligence quotient, as well as greater social impairment and higher percentage meeting cut-off score for autism on Autism Diagnostic Interview-Revised. BDNF haploinsufficiency is also associated with lower scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people. These findings suggest that BDNF plays a role in human cognitive functioning and nociception. A treatment study using a BDNF agonist in patients with BDNF haploinsufficiency is also under development. We have also been studying patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Patients with PWS typically present with hypotonia and poor feeding in the neonatal period followed by marked weight gain and severe hyperphagia between the ages of 1-5 years. PWS is also associated with cognitive impairment and behavioral abnormalities. We conducted a pilot study comparing 13 children with PWS versus 13 age/sex-matched lean controls and 13 age/sex/body mass index (BMI)-matched obese controls (J Clin Endocrinol Metab 2010;95(7):3532-6). We observed that patients with PWS had lower serum BDNF compared to the lean controls (p=0.03) as well as the obese controls (p=0.01). Lower serum BDNF suggests insufficient central nervous system production of BDNF because BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neurocognitive abnormalities observed in PWS. We are currently conducting a study in a larger cohort of patients with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 BMI-matched controls to confirm these findings and to examine possible associations between cognitive function and serum BDNF concentrations. In collaboration with Dr. Biesecker's research group, we have been studying patients with Bardet-Biedl syndrome (BBS), a cilopathy associated with obesity. In animal models of cilia dysfunction, defects in leptin receptor trafficking and signaling have been reported. In our human studies (J Clin Endocrinol Metab 2011; 96(3):E528-35), we have observed that patients with BBS (n=50) have nearly two-fold higher serum leptin concentrations (p<0.001) compared with age/sex/race/BMI-matched control subjects (n=100). Hyperleptinemia out of proportion to degree of adiposity suggests that leptin resistance may be the causative etiology of obesity in BBS. We are currently seeking to replicate this observation in patients with Alstrom and Joubert syndromes, disorders that are distinct from BBS but are also associated with cilia dysfunction. In addition, we are investigating the role of BDNF in other conditions associated with childhood obesity (e.g. melanocortin 4-receptor mutations and Smith-Magenis syndrome) and/or neurocognitive impairment (e.g. autism spectrum disorders - in collaboration with Dr. Swedo's research group). We are also studying the role of single nucleotide polymorphisms of the BDNF gene locus in body weight regulation and cognitive function in healthy adults and children from the general population. In collaboration with Dr. Kleinman's research group, we are examining the associations of BDNF genotype with BMI and hypothalamic BDNF expression in cadaveric brain tissue from adults with sudden death. Because of BDNF's potential role in pain perception, we are also collaborating with resarchers at the Walter Reed National Military Medical Center to explore possible associations between BDNF and phantom limb pain in patients who have had amputations.